symposium “triple therapy with boceprevir: from science to...

EASL endorsed conferenceWhite Nights of Hepatology 2013

Symposium “Triple therapy with boceprevir: from science to real life”June 6-7 Saint-Petersburg

Boceprevir use: from clinical trials to real life

K. Zhdanov

SVR Rates With BOC + PR According to Treatment History

0

20

40

60

80

100

SVR

(%)

Naive

63-66

Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. Bronowicki JP, et al. EASL 2012. Abstract 11.

Relapsers

69-75

Partial Responders

40-52

NullResponders

40

> > >

Main phase III clinical trials with boceprevir: SPRINT-2, RESPOND-2, PEG2a, PROVIDE, Anemia Management Study

SPRINT-2 and RESPOND-2 (Boceprevir): SVR by IL28B genotype and fibrosis stage in treatment-naḯve

and treatment-experienced GT1 CHC patients

Poordad F, et al. Gastroenterology 2012;143:608-618

77 83

30

1223

10086

25

66

5062

20

78

100

76

22

5867

CC F0-2 CC F3-4 CT F0-2 CT F3-4 TT F0-2 TT F3-4

1/843/56

61/71

38/49

5/6

1/4

5/5

31/103

59/89

79/104

5/10

2/9

8/35

20/32

22/38

1/1

1/5

4/6

4050

19 14

62

0

82 89

66

50

71

33

7967 71

89 91

40

CC F0-2 CC F3-4 CT F0-2 CT F3-4 TT F0-2 TT F3-4PR48 BOC RGT BOC/PR48

4/10

14/17

11/14

1/2

8/9

4/6

4/21

31/47

39/55

1/7

5/10

8/9

5/8

5/7

10/11

1/3

2/5

RESPOND-2

SPRINT-2

SPRINT-1 (Boceprevir): SVR and RVR by Lead-in phase

with PegIFN/RBV

666260

38

SVR RVR

Lead-in No Lead-in

p<0.001

Kwo PY et al., Lancet 2011;376:705-16 Poordad F. N Engl J Med. 2011; 364:1195-1206

SVR

(%)

86

48 P/R

SPRINT-2:SVR in patients with RVR

4856

89

BOC RGT

91

BOC/P/R48

166182

170190

0

20

40

60

80

100

nN =

4

51

0

2528

81

33

73

38

79

34

79

0

20

40

60

80

100

HCV RNA < 1 log10decline

HCV RNA > 1 log10decline

HCV RNA < 1 log10decline

HCV RNA > 1 log10decline

SVR

(%)

PR48 BOC RGT BOC/PR48

SPRINT-2 RESPOND-2

3/832797

3695

133260

203252

200254

1546

1544

1767

80110

901140/12

nN =

Bacon BR, et al. Hepatology 2010;52(Suppl.):430A Poordad F, et al. N Engl J Med 2011;364:1195-206

SVR by Response at Wk 4 in Lead-in Arms

SVR by Response at Wk 4 in Lead-in Arms by Previous Response Category

1. Bronowicki JP, et al. EASL 2012. Abstract 11. 2. Foster G, et al. EASL 2011. Abstract 6.

Partial NRRelapsers Null NRPROVIDE (BOC)[1]

n/N = N/A

56†64

72

36

55

0

20

40

60

80

100

< 1 log ≥ 1 log14/22 13/36 5/9 36/50 6/11

† 40% of previous relapsers still receiving treatment

REALIZE (TVR)[2]

SVR

(%) 62

94

56 59

15

54

0

20

40

60

80

100

< 1 log ≥ 1 log8/13 10/18

106/113 16/27 15/286/41

Early IFN Response (Lead-in) Further Defines Likelihood of SVR for Non-CC Pts

A > 1 log10 decrease in HCV RNA at Wk 4 of therapy is the strongest predictor of SVR

0/2

2/3

2/4

56/75

83/102

58/72

1/27 19/

5120/45

37/117

83/111

109/133

1/20 6/

2510/25

13/26

23/28

26/34

CC CT TT

≥ 1 log ≥ 1 log ≥ 1 log

SVR

(%)

SPRINT-2 and RESPOND-2 Combined

100

80

60

40

20

0

67

50

7581 81

4

3744

32

7582

524

4050

8276

PegIFN-α2b/RBVBOC + pegIFN-α2b/RBV RGTBOC + pegIFN-α2b/RBV 48 wks

< 1 log < 1 log < 1 log

n/N=

Poordad F, et al. Gastroenterology. 2012;143:608-618.

1825

52 55

13 14

77

87

0 0

50

18

0

20

40

60

80

100

SPRINT-2 RESPOND-2 SPRINT-2 RESPOND-2

SVR

(%)

BOC RGT BOC/PR48 PR48

HCV RNA <1.0 log10 decline HCV RNA ≥1.0 log10 decline

03

312

17

918

1121

2026

211

1120

2023

05

211

216

SVR by Response at Wk 4 in Lead-in Arms and cirrhosis

Bruno S. et al., EASL 2011

Predictive Value of Wk 8 Response to BOC for SVR in Poorly IFN-Responsive

Patients Poor IFN responsiveness: < 1 log HCV RNA decline by Wk 4 of

PegIFN/RBV lead-in in BOC arms of phase III trials• Among these patients, 0% with < 3 log decline in HCV RNA at Wk 8 of

therapy achieved SVR

Poordad F, et al. Gastroenterology. 2012;143:608-618.

100

80

60

40

20

0

SVR

* (%

)

RESPOND-20

3821

50

n/N = 0/16 3/8 6/28 10/20 0/28 2/23 23/70 15/31

09

3348

0/44 5/31 29/98 25/51

016

3049

91

10/11 23/29

79

33/40

83

SPRINT-2 Combined

< 3 3-4 4-5 > 5 UndetectableWk 8 Log10 HCV RNA Decline From Baseline

*BOC arms combined.

Meta-analysis of BOC + P/R in Pts With GT 1 HCV and Compensated Cirrhosis

• Pooled analysis of SPRINT-2, RESPOND-2, PEG2a, PROVIDE, and Anemia Management Study, including treatment-naive and treatment-experienced patients

Vierling JM, et al. EASL 2013. Abstract 1430. Reproduced with permission.

100

80

60

40

0

SVR

24 (%

)

F0-2 F3 F4Metavir Fibrosis Score

BOC + P/RP/R

n = 1638 436 107 22 180 32

66

28

54

26

55

1720

Meta-analysis of BOC + P/R in Pts With GT 1 HCV and Compensated Cirrhosis

• Cirrhotics more frequently experienced SAEs, dose modification due to AEs and/or anemia, infections, Hb < 10 g/dL, grade 2/3 thrombocytopenia, grade 3/4 neutropenia

Vierling JM, et al. EASL 2013. Abstract 1430.

Event, %BOC/P/R P/R

F0-2 F3 F4 F0-2 F3 F4SAE 12 12 18 8 14 6Dose mod due to AEs 39 40 43 22 23 41 Due to anemia 25 27 32 13 5 16

Discontinue due to AEs 14 15 16 14 5 3 Due to anemia 2 4 1 1 0 0

Transfusions 2 7 7 < 1 0 0Life-threatening treatment-emergent AEs 2 3 4 1 0 0

Death < 1 0 1 1 0 0

Duration therapy and futility rules in different groups of GT1 HCV patients

P/R P/R/BOC

P/R P/R/BOC P/R

P/R P/R/BOC

P/R P/R/BOC P/R

P/R P/R/BOC P/R

P/R P/R/BOC

Treatment-naḯve

Relapse/Partial response

Null response/Cirrhosis

FDA

EMA

+

+

-

-

Futilityrules

HCV RNA> 100 IU/ml

HCV RNA> LLDLabel

0 4 8 12 24 28 36 48

Maasoumy B., Manns M. Liver Intern, 2013: 33 (1); 14-22

1. Chen EY, et al. AASLD 2012. Abstract 133. 2. Bichoupan K, et al. AASLD 2012. Abstract 1755.

50

40

30

20

10

0

Patie

nts

(%)

n/N =

18

498 GT1 Patients Evaluated[1]

Started Therapy

2217

1169/407

89/407 43/407

Did Not Start

PatientChoice

Wait forBetter

Therapies

MildDisease

Higher Discontinuation Rates in Real-World Settings Than in Clinical

Trials

D/CBeforeWk 12

21

40

30

20

10

0

91/498

D/C TVR < 12 wks

58/174

33[2]

21

36/174

174 GT1 Patients StartedTVR-Based Triple Therapy[2]

Due to AEs

56% - 1a37% - F341% - F427% - non-responders

HCV-TARGET: Triple Therapy (TVR or BOC + P/R) in a Broad Patient Population

• Interim analysis of longitudinal observational study of sequentially enrolled patients in academic and community medical centers in North America

Fried MW, et al. EASL 2013. Abstract 818.

Patient Disposition, n (%) DAA + P/R(N = 1919)

Patients in current analysis 1457 Patients with cirrhosis 550 Still on treatment, < 16 wks 139 (6) Still on treatment, > 16 wks 664 (46) Completed full course 319 (22)

Patient Disposition DAA + P/R(N = 1457)

Early discontinuation, % (n) 335 (23) Lack of efficacy 8 Adverse event 9 Other reasons 5 Multiple reasons 2

HCV-TARGET: Baseline Characteristics


Patient Characteristic Cirrhotic(n = 550)

Noncirrhotic(n = 787)

40-64 yrs of age, % 84 80Male, % 69 55White, % 78 70Genotype, % 1a 1b Not otherwise specified

581919

582213

Treatment naive, % 41 52Mean hemoglobin > 12 g/dL 94 84Mean platelets, cells/mm3 126,000 203,000Mean total bilirubin, mg/dL (range) 1.0 (0.2-5.0) 0.63 (0.2-2.5)Mean albumin, g/dL (range) 3.9 (1.4-5.0) 4.2 (1.9-5.4)Mean Meld score (range) 8 (6-22) N/APresence of varices, % 33 1

HCV-TARGET: Virologic Response by Previous Treatment Category

• In interim analysis, on-treatment efficacy of boceprevir in real-world setting comparable to registrational trials only in treatment-naЇvepatients

Fried MW, et al. EASL 2013. Abstract 818. Reproduced with permission.

n = 101 79 28 25 21 16 37 32

100

80

60

40

20

0

BOC Wk 8BOC Wk 12

Treatment Naive

Previous Relapser

Previous Partial or Null Response

UnknownResponse

61

78

25

48

15

44 43

63

Und

etec

tabl

e H

CV

RN

A (%

)

HCV-TARGET: Safety Assessment of Triple Therapy in Patients With Cirrhosis


Event, % Cirrhotic(n = 550)

Noncirrhotic(n = 787)

SAE 8 8Death, n 2 1Early discontinuation Due to adverse event Due to lack of efficacy

264431

213338

Decompensation 11 1Infection 21 24Severe rash (grade 3/SCAR) 2 1Hemoglobin < 8.5 g/dL 20 14RBV dose reduction 42 31EPO 10 10Transfusion 11 5

SVR12 rates and safety of triple therapy including telaprevir or boceprevir in 485 cirrhotic non responders treated in the

French Early Access Program (ANRS CO20-CUPIC)

H Fontaine1, C Hézode2, C Dorival3, D Larrey4, F Zoulim5,V de Ledinghen6, V Canva7, L Alric8, M Bourlière9, S Pol1, T Poynard10, G Riachi11, PH Bernard12, JJ Raabe13,

J Gournay14, S Métivier15, JM Pawlotsky16, D Samuel17, Y Barthe3, F Carrat3, JP Bronowicki18, for the ANRS CO 20 CUPIC study group.

1.Hôpital Cochin, Paris, 2. Hôpital Henri Mondor, Créteil, 3. UMR-S 707, Paris, 4. Hôpital Saint-Eloi, Montpellier, 5. INSERM U871, Lyon, France, 6.Hôpital Haut Lêvèque, Bordeaux, France 7. Hôpital Clude Hurriez, Lille, France, 8. Médecine Interne, Hôpital Purpan, Toulouse, 9. Fondation Saint-Joseph, Marseille, France, 10. Hépatologie, Hôpital de la Pitié-Salpétrière, Paris, France 11. Hôpital Charles Nicolle, Rouen, France, 12. Hôptal Saint-André, Bordeaux, France, 13. Hôpital Bon Secours, Metz, France, 14. Hôpital Universitaire de Nantes, Nantes, France 15. Hépatogastroentérologie, Hôpital Purpan, Toulouse, France, 16. Hôpital Henri Mondor, Créteil, France 17. Hôpital Paul Brousse, Villejuif, France 17. Hôpital de Brabois, Nancy, France

Treatment regimen

Peg‐IFN α‐2a + RBVTVR + Peg‐IFN α‐2a + RBV Follow-up

484 160 128Weeks

72

SVR assessment

BOC + Peg‐IFN α‐2b + RBV Follow-upPeg-IFN + RBV

36

http://www.afssaps.fr/var/afssaps_site/storage/original/application/4b8c53711bab9d8f7d4c3f947caa90f6.pdfhttp://www.afssaps.fr/var/afssaps_site/storage/original/application/fa78af08e029caf9d82bcd9d3e77eb09.pdf

BOC: 800 mg/8h; Peg‐IFNα‐2b: 1.5 µg/kg/week; RBV: 800 to 1400 mg/day

TVR: 750 mg/8h; Peg‐IFNα‐2a: 180 µg/week; RBV: 1000 to 1200 mg/day

SVR12

60

N = 190

N =295

NO RANDOMISATION

Fontaine H, EASL 2013

Patient baseline demographics and disease characteristics

Characteristic Telaprevir N=295

Boceprevir N=190

Male, % 201 (68) 133 (70)

Mean age, years (range)Mean BMI, SD (kg/m2)

57 (27-83)26.5 (18.2-40.4)

57 (34–79)26.2 (18.1-39.4)

HCV genotype 1 subtype, n (%) 1a1bOther

98 (33)162 (55)33 (11)

77 (41)96 (51)16 (8)

HCV RNA ≥800,000 IU/mL, n (%) 182 (62) 122 (64)Treatment history, n (%)

Prior relapsePrior partial responsePrior null responseOthers

116 (39)135 (46)28 (10)15 (5)

85 (45)80 (42)9 (5)

16 (8)

Exclusion criteria, n (%)REALIZERESPOND-2

99 (34)137 (46)

52 (27)73 (38)


Patient baseline demographics and disease characteristics

Characteristic Telaprevir N=295

Boceprevir N=190

Child-Pugh score A/B, n (%)* 280 (95) / 6 (2) 177 (93) /1 (1)

MELD score, mean (range) 8.1 (6-22) 8.1 (6-28)

Prothrombin time ratio, mean % (range) 86 (27–100) 87 (23–100)

Serum albumin g/L, mean (range) 40.0 (20.7–53.2) 40.7 (27.0–50.3)

Total bilirubin μmol/L, mean (range) 15.5 (4.0–73.0) 15.2 (4.0–78.0)

Hb level g/dL, mean (range) 14.5 (9.0–19.7) 14.8 (10.8–18.4)

Neutrophils, mean (range) (109/mm3) 3.3 (0.8-8.5) 3.2 (0.5-8.5)

Platelet count, mean (range) (103/mm3) 151(18–604)

144(34–346)

Esophageal varices, n (%) 51/145 (35.2) 37/97 (38.1)* Missing data : 21 Fontaine H, EASL 2013

CUPIC: Telaprevir or Boceprevir + P/R in GT 1 Treatment-Experienced

Cirrhotics• French compassionate use program for early access to TVR and BOC before

approval

Fontaine H, et al. EASL 2013. Abstract 60. Reproduced with permission.

n/N = 118/295

79/190

61/116

43/85

43/135

32/80

8/28 1/9

100

80

60

40

20

0

SVR

12 (%

)

Overall Relapsers Partial Response Null Response

40 4153 51

3240

29

11

Telaprevir + P/RBoceprevir + P/R

Previous Response to P/R

p = 0.003

Boceprevir: treatment failure

0102030405060708090

100

Viro

logi

cal f

ailu

re (

%)

40/111 12*/11130/111

Premature discontinuation

Relapse Breakthrough

36%

11%

27%

29/111

26%

*10 without failure

Premature discontinuation

due to a detectableHCV RNA


SVR12 (ITT) – 41%

Boceprevir: SVR12 according to

HCV subtype initial viremia

0

10

20

30

40

50

60

70

80

90

100

SVR

12

(ITT

) (%

)

2477

4996

616

G1a G1b G1undetermined

31%

51%

37%

0

10

20

30

40

50

60

70

80

90

100

SVR

12

(ITT

) (%

)2765

51122

41% 42%

< 800,000 IU/mL ≥ 800,000 IU/mL

p = 0.03 NS


Boceprevir: SVR12 according to

HCV RNA decline at W4 RVR at W8

0

10

20

30

40

50

60

70

80

90

100

SVR

12

(ITT

) (%

)2693

5387

28%

55%

No RVR RVR

0

10

20

30

40

50

60

70

80

90

100

SVR

12

(ITT

) (%

)

34102

4588

33%

51%

< 1 log10 ≥ 1 log10

p = 0.018 p = 0.0002


Patients, n (% patients with at least one event) Boceprevir n = 190

Serious adverse events (SAEs)* 321 in 97 patients (51.0%)

Premature discontinuation / due to SAEs 80 (42.1%) / 27 (14.2%)

Death (1 pulmonary infection, 1 anevrysmal beeding, 1 septicemia) 3 (1.6 %)

Infection (Grade 3/4) 8 (4.2 %)

Hepatic decompensation (Grade 3/4) 9 (4.7 %)

Rash (grade 3/4) 2 (1.0 %)

Anemia (Grade 3/4: Hb < 8 g/dL) 19 (10.0 %)

EPO use / blood transfusion 119 (62.6 %) / 26 (13.7 %)

GCSF use 13 (6.8 %)

TPO use 3 (1.6 %)

Boceprevir : SVR12 safety findings


Duration therapy and futility rules in different groups of GT1 HCV patients

P/R P/R/BOC

P/R P/R/BOC P/R

P/R P/R/BOC

P/R P/R/BOC P/R

P/R P/R/BOC P/R

P/R P/R/BOC P/R/BOC

Treatment-naḯve



FDA

EMA

+

+

-

-

Futilityrules

HCV RNA> 100 IU/ml

HCV RNA> LLD

Label

Personalized

< 1 log declineNull response +

Cirrhosis

< 3 log decline

0 4 8 12 24 28 36 48

Shortening of treatment,if eRVR and poor P/R/BOC tolerability

Shortening of treatment (or P/R only), if poor P/R(or BOC) tolerability

Personalized

Maasoumy B., Manns M. Liver Intern, 2013: 33 (1); 14-22

Duration therapy and futility rules in GT1 HCV cirrhotic patients?

P/R P/R/BOC

P/R P/R/BOC P/R

P/R P/R/BOC

P/R P/R/BOC P/R

P/R P/R/BOC P/R

P/R P/R/BOC P/R/BOC

Treatment-naḯve



FDA

EMA

+

+

-

-

Futilityrules

HCV RNA> 100 IU/ml

HCV RNA> LLD

Label

Personalized

< 1 log decline

LLD < HCV RNA < 100 IU/ml

0 4 8 12 24 28 36 48

Shortening of treatment,if eRVR and poor P/R/BOC tolerability

Shortening of treatment (or P/R only), if poor P/R(or BOC) tolerability

Personalized

Maasoumy B., Manns M. Liver Intern, 2013: 33 (1); 14-22Bruno S., Mangia A. Dig Liv Dis, 2013: 45; 356-361

Conclusions1. Triple therapy with Boceprevir results in high SVR rates in treatment-naЇve

non-CC IL28B and relapse to prior pegIFN/RBV GT1 patients

2. Treatment-experienced GT1 patients with partial or null response to prior PegIFN/RBV and no significant liver damage can wait for new, more potent drugs

3. 4 weeks of pegIFN/RBV lead-in before Boceprevir lowers HCV RNA burden, identifies rapid responders who may not need DAA, provides useful information regarding likelihood of SVR with addition of PI and insight into tolerability of pegIFN/RBV backbone

4. HCV RNA < 3log decline at week 8 (week 4 after BOC addition using lead-in) has a strong negative predictive value for SVR in poorly IFN-responsive patients

5. The expected benefits associated with triple combination with Boceprevirshould be balanced with the risks of severe adverse events in cirrhotic patients, particularly in prior null responders and HCV RNA < 1log decline at week 4 after lead-in

6. Unclear algorithms for G1 cirrhotic patients both naЇve and treatment-experienced (relapse and partial response to prior pegIFN/RBV) if: - HCV RNA < 1log decline at week 4 after lead-in - HCV RNA > 1log decline at week 4 after lead-in and detectable at week 8 after

Boceprevir addition (but < 100 IU/ml)

symposium “triple therapy with boceprevir: from science to...

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